Glucocorticoids (GC) are known inhibitors of wound healing, suppressing many wound healing regulators, such as IL-1, TNFα, KGF, PDGF, FGF, MME and collagens (Oishi et al. (2002) Brit. J. Dermatol. 147:859-68; Madlener et al. (1998) Exp. Cell Res. 242:201-10). Glucocorticoids affect all of the essential steps of normal wound healing, including the early inflammatory phase, matrix deposition, and angiogenesis.
The hypothalamic-pituitary-adrenal (HPA) axis is responsible for the production of steroid hormones with glucocorticoid activity. The hypothalamus controls the secretion of ACTH from the pituitary gland, which in turn, stimulates the secretion of cortisol by the adrenal gland (Tsigos et al. (2002) J. Psychosomatic Res. 53:856-871).
In humans, cortisol is the most important steroid hormone with glucocorticoid activity. Adults secrete about 20 μg of cortisol daily in a pronounced circadian cycle. Plasma levels of cortisol vary from 5-25 μg/dL, but only a fraction of this hormone is physiologically active as more than 95% of circulating plasma cortisol is bound reversibly to circulating plasma proteins.
Glucocorticoid shares a synthesis pathway with aldosterone and androgens in the adrenal gland proceeding up until the final step. The final step specific for glucocorticoids involves the steroid 11 beta-hydroxylase (CYP11B), a mitochondrial chytochrome P-450. An additional fine-tuning mechanism in the cortisol pathway involves 11β-hydroxysteroid dehydrogenase (11β-HSD) HSD11B1/HSD11B2 enzymes. These two distinct isozymes of 11β-HSD catalyze the interconversion of hormonally active cortisol and inactive cortisone. HSD11B1 converts inactive cortisone to active cortisol. HSD11B2 converts active cortisol to the inactive form of cortisone, thus preventing cortisol binding to the receptor (Quinkler et al. (2003) J. Clin. Endocrinol. Metab. 88(6):2384-92; Albiston et al. (1994) Mol. Cell. Endocrinol. 105:R11-R17). Recent data suggests that tissue-specific regulation of GCs, mediated via differential regulation of the enzyme HSD11B1, can play an important role in defining tissue-specific responses during the resolution of inflammation (Hardy et al. (2006) Arthritis Res. Ther. 8:R108).
Very little is known about steroidegenesis in non-adrenal tissue. However, the concept of skin as an endocrine organ is not new (Zoubolis (2000) Hormone Res. 54:230-242). Skin expresses most hormone receptors, and is able to metabolize, activate, and inactivate hormones. Epidermal cells have been implicated in the production of endogenous hormones equivalent to the HPA axis, including corticotrophin releasing hormone (CRH) and the proopiomelanocortin (POMC) derived peptides, MSH, adrenocorticotropic hormone (ACTH), and β-endorphin. (Ermak et al. (1997) J. Invest. Dermatol. 108:160-165; Slominski et al. (1995) FEBS Letters 374:113-116). Furthermore, isolated hair follicles secrete substantial levels of cortisol and display HPA axis-like regulatory feedback systems (Ito et al. (2005) FASEB 19(1)1332-34). It has also been shown that fibroblasts and melanocytes produce cortisol in vitro (Slominski et al. 2006) J. Invest. Dermatol. 126(5):1177-8; Slominski et al. (2005) J. Physiol. Endocrinol. Metabol. 288(4):E701-06).
Glucocorticoid activates the glucocorticoid receptor (GR) pathway. Upon activation, the GR, bound to the glucocorticoid, translocates from the cytoplasm of the cell to the nucleus. The GR pathway is found in many types of cells, including epidermis. The GR is involved, at least, in the NF-kB pathway and may decrease inflammation, in part, by blocking the binding of this transcriptional factor to pro-inflammatory genes.
Non-healing wounds are reaching epidemic proportions among the elderly, the disabled, and those with diabetes (Brem et al. (2003) Surg. Tech. Int. 11: 161-167). Chronic ulcers are characterized by physiological impairments, manifested in delays in healing, which results in severe morbidity. Not only do these chronic ulcers significantly impair an affected person's life, the cost of caring for such chronic wounds is burdensome. Over twenty-five billion dollars was spent in the United States alone on the treatment of chronic wounds. (Williams et al. (2005) Wound Repair Regen. 13:131-137; Steed et al. (1996) J. Amer. Coll. Surg. 77:575-586).
Contributing to the problem of chronic non-healing wounds is the lack of understanding of the molecular mechanisms and the pathogenesis of the impaired healing of such wounds. Until now, the role of glucocorticoids in the development of chronic wounds remained unknown.